tbuckley/cabot-search huggingface dataset:
Abstract P6-14-01: Invasively distinct subpopulations cooperate via a laminin-332/Rac1 axis in triple-negative breast cancer
Authors: Sung Bo (Joseph) Yoon, Janna Mouw, Luxiao Chen, Hao Wu, Adam Marcus
Journal: Cancer Research (2023)

Abstract Intratumoral heterogeneity poses a significant hurdle for cancer treatment, yet is under-characterized in the context of tumor invasion. Cancer cells from solid tumors can invade through two predominant modes: collective invasion, whereby cancer cells invade in multi-cellular packs or streams marked by intact cell-cell junctions; and single-cell invasion, whereby cells invade independently without intercellular adhesion. We have observed that collective and single-cell invasion co-occur within the same tumor microenvironment in triple-negative breast cancer, suggesting that invasive heterogeneity supports cooperative behavior between tumor subpopulations. To test this, we used a novel, published technique developed by the lab (SaGA) to isolate pure subpopulations of 4T1 cells that collectively invade (collectives) or single cells that invade alone (singles). 3-D spheroids of SaGA-purified collectives and singles exhibited almost exclusively collective and single-cell invasion, respectively, and these invasive phenotypes were retained over multiple passages. Integration of RNA sequencing and methylation array data obtained from RNA and DNA isolates, respectively, of collectives and singles revealed that collectives exhibit drastic overexpression and promoter hypomethylation of two laminin genes that form the laminin-332 complex, Lama3 and Lamc2. Additionally, an unbiased proteomic analysis of secreted proteins also revealed an overabundance of these laminins in collectives media. We found that singles have increased expression of integrin α6 and β4, which together have been found to specifically bind to laminin-332 to activate the Rac1 GTPase. Interestingly, our RNA sequencing data revealed a binary overexpression of a Rac1 GTPase, Prex1 in singles, suggesting that singles have enhanced Rac1 activation when compared to collectives with the potential for hyperactivation upon laminin-332 binding. Indeed, laminin-332 resulted in higher GTP-bound Rac1 in singles and subsequently increased invasion of singles in 3-D models. Additionally, laminin-332 induced cell elongation at the leading edge of singles spheroids, which was reversable by treatment with a Rac1 inhibitor. Together, our data suggests that distinct subpopulations amidst a heterogeneous tumor cooperate via laminin-332 and Rac1 to facilitate tumor invasion in metastatic triple-negative breast cancer. Citation Format: Sung Bo (Joseph) Yoon, Janna Mouw, Luxiao Chen, Hao Wu, Adam Marcus. Invasively distinct subpopulations cooperate via a laminin-332/Rac1 axis in triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-01.
Abstract P6-12-08: Identifying FOXA1 Binding Partners using Proximity Labeling
Authors: Rosemary N. Plagens, Shen Li, Christine A. Mills, Laura Herring, Hector L. Franco
Journal: Cancer Research (2023)

Abstract Approximately 75% of breast cancers are driven by the estrogen receptor alpha (ER), and despite the advent of endocrine therapy to block ER signaling pathways, a significant portion of women develop resistance to these drugs. The pioneer factor FOXA1 has been shown to facilitate nearly all DNA-binding events of ER in response to estrogen in ER+ breast cancer (ER+BC). Notably, up-regulation of FOXA1 is a hallmark of endocrine-resistant phenotypes and has been shown to reprogram enhancer elements, leading to an altered transcriptome. However, FOXA1 is a critical pioneer factor for multiple nuclear hormone receptors, aside from ER, and is implicated in regulation of important factors such as HER2 and the androgen receptor (AR). With the diverse array of breast cancer molecular subtypes displaying complex interplay between ER, HER2, AR, PR, and other hormone receptors, describing the complete ensemble of FOXA1 binding partners in various contexts, such as endocrine-resistant tumors, is of increasing importance. To define a comprehensive catalog of FOXA1 binding partners under basal conditions, we generated MCF-7 cell lines stably expressing constructs of FOXA1 fused at its N- or C-terminus to the biotin ligase miniTurbo. Using proximity labeling coupled with mass-spectrometry, we have comprehensively cataloged binding partners of FOXA1, including many expected proteins such as ER, AR, MLL3, YAP1, and GATA-3. Moreover, we have discovered more than 150 previously unidentified binding partners of FOXA1, which may exert profound effects on FOXA1 function. Importantly, high hazard ratios and significant dependencies are associated with several of these new binding partners, such as subunits of a previously described histone deacetylase (HDAC) complex containing genetic suppressor element 1 (GSE1) and lysine-specific histone demethylase 1A (KDM1A). Genomic approaches are currently underway to characterize where in the genome FOXA1 is interacting with these novel proteins and to guide future exploration into the physiological significance of these interactions. Integrating biochemical, molecular, and genomic approaches, we have potentially highlighted new mechanisms of FOXA1, which could have significant clinical impact in the future. Citation Format: Rosemary N. Plagens, Shen Li, Christine A. Mills, Laura Herring, Hector L. Franco. Identifying FOXA1 Binding Partners using Proximity Labeling [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-12-08.
Abstract P3-01-10: Going beyond the median: Estimating survival times for patients with hormone receptor positive, metastatic breast cancer commencing endocrine therapy
Authors: Andrew O. Parsonson, Sunit Sarkar, Lauren Brown, Belinda Kiely, Anuradha Vasista
Journal: Cancer Research (2023)

Abstract Background: Oncologists are often asked to provide information about expected survival times for patients with metastatic breast cancer (MBC). We have previously demonstrated that using estimates of best-case, typical and worst-case scenarios for survival to explain life expectancy conveys more meaning and hope than simply providing single point estimates of the median overall survival (OS). Our aim was to assess whether using simple multiples of the median could accurately assess scenarios for survival for patients with estrogen receptor (ER) positive, MBC starting endocrine therapy (ET) using simple multiples of the median. Methods: We systematically searched for randomised trials of ET for ER positive MBC. We then recorded the following percentiles (representative scenarios) from the OS curve of each trial using UN-SCAN-IT® graph digitising software: 90th (worst-case), 75th (lower-typical), 50th (median) 25th (upper-typical), and 10th (best-case). We assessed the accuracy of estimating these percentiles for each OS curve by multiplying the median OS by four simple multiples: 0.25 (to estimate the 90th percentile), 0.5 (75th), 2 (25th) and 3 (10th). Estimates were deemed accurate if within 0.75 -1.33 times the actual value. Results: We identified 24 trials with 10,068 patients. The median OS (interquartile range [IQR]) was: 61.3 months (53.4-64.8) for first-line ET with cyclin-dependant kinase 4/6 inhibitors (CDK4/6i) (4 treatment groups); 42.6 months (40.9-50.4) for first-line ET alone (23 treatment groups) and 29.2 months (24.8-33.4) for subsequent line ET (21 treatment groups). The median OS (IQR) for each scenario for first-line ET with CDK4/6i was: worst-case 17.4 months (13.8-20.7); lower-typical 32.5 months (29.3-34.9); upper-typical and best-case percentiles were not available. Simple multiples of the median OS accurately estimated the 90th percentile in 79%; 75th percentile in 93%; and 25th percentile in 76% of curves. The 10th percentile was only available for four OS curves and could not be accurately assessed. Conclusion: Using simple multiples of the median OS to estimate and explain survival times to patients with MBC starting ET, is accurate and meaningful. Longer follow-up of trials is required to help clinician’s estimate the best-case scenario for these patients. Citation Format: Andrew O. Parsonson, Sunit Sarkar, Lauren Brown, Belinda Kiely, Anuradha Vasista. Going beyond the median: Estimating survival times for patients with hormone receptor positive, metastatic breast cancer commencing endocrine therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-10.
Abstract P6-05-24: Implementing System Solutions for Survivorship Care Plans
Authors: Dina Alnabulsi, Gloria L. Jackson, AnaMaria Lopez
Journal: Cancer Research (2023)

Abstract Background: A survivorship care plan (SCP) is a detailed cancer care summary and future care plan that is generally given to a patient upon completion of adjuvant treatment for a cancer diagnosis. The initial goals of SCPs were to educate patients and other health care professionals about the treatments received, make them aware about potential long-term effects of therapy, and emphasize recommendations for future cancer screening and care (1). Due to numerous barriers—scheduling, staffing, and lack of awareness—SCPs are not delivered to all eligible patients. To address this unmet need our multidisciplinary breast clinic (MDBC) established an Advanced Practice Professional (APP) Survivorship Clinic. With the acute impact of the COVID-19 pandemic, survivorship referrals decreased. We, therefore, developed and implemented system solutions to address SCP access. Methods: System solutions include partnering with the Cancer Registry to provide the list of patients potentially in need of survivorship visits, partnering with pharmacy to confirm patient eligibility, creating specifically designated telemedicine survivorship visits in our electronic scheduling system, prospectively scheduling persons identified, engagement of APPs across the MDBC, and establishing a single coordinating point. Numbers of SCPs delivered are tracked monthly and patient satisfaction is assessed through data collected Press Ganey surveys. Results: This presentation will share our process interventions and outcomes as they mature. Our early data demonstrate the efficacy of the workflow and appear promising. Conclusion: We anticipate that system-based solutions will provide more patients with SCPs and demonstrate patient satisfaction. Blaes AH, Adamson PC, Foxhall L, Bhatia S. Survivorship Care Plans and the Commission on Cancer Standards: The Increasing Need for Better Strategies to Improve the Outcome for Survivors of Cancer. JCO Oncol Pract. 2020 Aug;16(8):447-450. doi: 10.1200/JOP.19.00801. Epub 2020 Apr 8. Erratum in: JCO Oncol Pract. 2020 Nov;16(11):774. PMID: 32267803. Gache, K., Leleu, H., Nitenberg, G. et al. Main barriers to effective implementation of stroke care pathways in France: a qualitative study. BMC Health Serv Res 14, 95 (2014). https://doi.org/10.1186/1472-6963-14-95 Citation Format: Dina Alnabulsi, Gloria L. Jackson, AnaMaria Lopez. Implementing System Solutions for Survivorship Care Plans [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-24.
Abstract P6-14-15: PD-L1 expression regulated by JAK/STAT signaling pathway contributes to cell migration and invasion in breast cancer
Authors: Junqing Chen
Journal: Cancer Research (2023)

Abstract Background: Programmed death-ligand 1 (PD-L1) implicated in tumor immune evasion and predictive biomarker in immunotherapy is widely recognized, however, the role of PD-L1 in modulating tumor invasion remains largely unexplored. PD-L1 expression on tumor tissue is usually limited by the invasiveness, tumor heterogeneity as well as insufficient tumor tissue samples, while PD-L1 expression on circulating tumor cells (CTCs) might overcome the limitation. In the present study, we aimed to investigate the role and mechanism of PD-L1 in regulating the migration and invasion of breast cancer cells and to evaluate PD-L1 expression on CTCs in metastatic breast cancer patients. Methods: The expression level of PD-L1 in MCF-7 cells and MDA-MB-231 cells was assessed by quantitative real-time RT-PCR and Western Blot. Gain-of-function and loss-of-function study on cell migration and invasion abilities were carried out by overexpression of PD-L1 or silencing PD-L1. PD-L1 expression on CTCs in thirty-six metastatic breast cancer patients were detected. A novel staining procedure which included fluorescent glucose analog staining for CTC enumeration and immunostaining targeting CD45, vimentin and PD-L1 were analyzed. Survival curves were estimated by the Kaplan-Meier method and the log-rank test was used to compare between groups. All tests were two-sided, and p values were considered significant at the 0.05 level. Results: Compared with MCF-7 cells, PD-L1 mRNA and PD-L1 protein expression were significantly increased in MDA-MB-231 cells. Down-regulation of PD-L1 expression in MDA-MB-231 cells inhibited the migration and invasion of MDA-MB-231 cells, while overexpression of PD-L1 in MCF-7 cells increased the migration and invasion of MCF-7 cells. In addition, we found that PD-L1 expression was regulated by JAK/STAT signaling pathway. PD-L1 expression on CTCs in metastatic breast cancer patients was associated with triple negative breast cancers subtype (P=0.013). High expression of PD-L1 on CTCs in metastatic breast cancer patients was correlated to poor overall survival (HR=3.165, 95%CI: 1.121-8.938, P=0.029). Conclusion: Our results indicate that high expression of PD-L1 contributes to cell migration and invasion in breast cancer cell possibly partially through JAK/STAT signaling pathway. The PD-L1 expression on CTCs might serve as a promising non-invasive prognostic biomarker in patients with metastatic breast cancer. Citation Format: Junqing Chen. PD-L1 expression regulated by JAK/STAT signaling pathway contributes to cell migration and invasion in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-15.
Abstract P3-05-57: Lymphatico-venous communications and rhythmic, respiratory pressure changes influence the incidence of metastatic disease at presentation in solid tumours
Authors: Rajendra Badwe, Shalaka Joshi, Rohini Hawaldar, Rohan Chaubal, Atanu Bhattacharjee, Vaibhav Vanmali, Nita S. Nair, Sudeep Gupta
Journal: Cancer Research (2023)

Abstract Background- Dissemination of cancer cells and their colonization at distant sites (metastases) is the primary cause of death in patients with solid tumors. Despite of popular theories of cancer metastases, there are several lacunae in our understanding of extent of Metastatic Disease at Presentation (MDP). The aim of this study was to evaluate if organ sites could be grouped together based on the available knowledge extent of lympho-vascular communication (LVC) and probable respiratory pressure changes they undergo and whether this correlated with incidence of MDP. Methods- We analyzed a prospectively maintained database of patients with solid tumors presenting between January and December 2017 at our tertiary care cancer center. The tumors were hypothetically divided into four regions (R) depending on extent of LVC and respiratory pressure changes. All patients had clinico-radiological staging after pathological confirmation of cancer. The hypothetical region grouping R1-R4 was independently evaluated by unsupervised k-means clustering. The incidence of MDP was compared in subgroups defined by primary tumor stage, anatomical region, histology, gender, and age using logistic regression. Results- Of 17,467 patients included with median age 54 years, 6714 (38.4%) had MDP. The incidence of M1 disease in R1 vs R2 vs R3 vs R4 regions, older (&amp;gt;50 years) vs younger Conclusion- Primary anatomical regions defined by LVC and respiratory pressure changes; primary tumor histology (type and grade) and male gender are significant determinants of MDP in solid tumors. Region grouping of solid organs based on extent of lymphaticovenous communications and rhythmic respiratory pressure changes and % MDP Citation Format: Rajendra Badwe, Shalaka Joshi, Rohini Hawaldar, Rohan Chaubal, Atanu Bhattacharjee, Vaibhav Vanmali, Nita S. Nair, Sudeep Gupta. Lymphatico-venous communications and rhythmic, respiratory pressure changes influence the incidence of metastatic disease at presentation in solid tumours [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-57.
Abstract P1-09-10: Factors associate with borderline or invaded margins in breast cancer surgery at the Val d’Aurelle Montpellier CRLC
Authors: veronique M. Mboua Batoum, esther D. Dina Bell
Journal: Cancer Research (2023)

Abstract Factors associate with borderline or invaded margins in breast cancer surgery at the Val d’Aurelle Montpellier CRLC Véronique Mboua Batoum*, Esther Dina Bell, Christianne Nsahlai, Junie Annick Metogo Ntsama, Esther Juliette Meka, Marian Gutowski, Simon Thezenas, William Jacot *Corresponding autor : vbatoum@gmail.com Introduction: The inadequate status of the resection margins after breast cancer surgery is an important predictor of local tumor recurrence. The objective of our study was to determine the factors associated with positive or invaded resection margins. Methodology: Our retrospective study included a cohort of 652 patients with early invasive breast cancer who underwent breast cancer conserving surgery at the Val d’Aurelle Regional Cancer Center. We defined positive margins as those with a distance of less than or equal to 2 mm from the tumour. The data were analysed using STATA® 10.0 software. Results: In our study, The median distance from the tumour to the surgical resection site was 5mm [0.0 - 35.0mm]. Resection margins were positive in 208 patients (31.9%). The rate of positive resection margins was significantly higher in non-menopausal patientss (P =0,0050), in those with tumours less than 2 cm in size (P = 0,0004), with ductal carcinoma in situ (DCIS) component and without lymph node involvement (P =0,0082). Re-excision surgery was performed in 229 patients (35.1%). Conclusion: Consideration of each of these factors associated with positive resection margins shoud help the surgeons to perform a wider excision, in other to obtain clear resection margin during the initial breast cancer surgery. Key words: breast cancer, conservative surgery, resection margins, risk factors for positive margins Citation Format: veronique M. Mboua Batoum, esther D. Dina Bell. Factors associate with borderline or invaded margins in breast cancer surgery at the Val d’Aurelle Montpellier CRLC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-09-10.
Abstract P6-14-10: Jagged-1 promotes breast cancer metastasis through the lymphatic system
Authors: Benjamin Gordon, Bhairavi Swaminathan, LA Naiche, Jan Kitajewski
Journal: Cancer Research (2023)

Abstract While early detection of breast cancer (BC) has improved prognoses, there is an urgent need to improve outcomes for patients with distant metastatic disease. Higher expression of the Notch ligand JAG1 in primary BC tumors is strongly associated with lymph node metastasis and patient mortality, but causality is unclear. We show that JAG1 expression is higher in patients’ metastatic BC cells colonizing lymph nodes than in primary tumors, suggesting that tumor cells with high JAG1 are preferentially able to metastasize to lymph nodes. JAG1 expression is higher in a derivative of BC line MDA-MB-231 selected for tropism to lymph nodes (MDA231-LN) than in the parental line or derivatives with other tropisms. To determine the mechanism(s) of JAG1-mediated metastasis, we generated clonal JAG1 knockout cell lines from MDA231-LN cells with corresponding JAG1 rescue lines. We investigated the role of JAG1 in spontaneous metastasis under clinically relevant conditions by orthotopically implanting JAG1 knockout and expressing cells, resecting the primary tumor, and following long-term metastatic spread in a mouse model. Quantification of tumor cells in blood showed that survival, metastatic burden, and JAG1 expression did not correlate with the number of circulating tumor cells. Conversely, JAG1 expression drove an increase in lymph node and body-wide metastatic burden and a trend toward decreased survival. In this model metastatic cells were abundant throughout lymph vessels, suggesting lymphatics are the primarily route of dissemination. Preliminary transcriptional analysis suggests that JAG1 alters interactions with lymphatic endothelial cells (LEC), potentially via VEGF signaling, leading us to examine downstream events in co-cultures of LEC with lymphatically invasive BC lines. Deciphering tumor-lymphatic endothelial signaling events may open new avenues to target BC metastasis. Citation Format: Benjamin Gordon, Bhairavi Swaminathan, LA Naiche, Jan Kitajewski. Jagged-1 promotes breast cancer metastasis through the lymphatic system [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-10.